Recently, there have been advanced studies of inflammatory diseases, in which the α-4-integrin-dependent adhesion process takes part in the pathology thereof, such as rheumatoid arthritis, inflammatory enteritis, systemic erythematosus, multiple sclerosis, Sjögren's syndrome, asthma, psoriasis, allergy, diabetes, cardiovascular diseases, arterial sclerosis, restenosis, tumorigenic hyperplasis, tumor metastasis, and implant-rejection and accordingly, it has been expected that a compound having an α-4-integrin-inhibitory action should be developed and used as a therapeutic agent or a prophylactic agent.
The applicant of this invention has developed an invention relating to a novel phenylalanine derivative which has an α-4-integrin-inhibitory activity and which would be considered to be highly useful as an agent for treating or preventing an inflammatory disease, in which the α-4-integrin-dependent adhesion process takes part in the pathology thereof and the applicant has already filed a patent application (see Patent Document 1 specified below). In this patent application, there has been reported, as a method for the preparation of such a phenylalanine derivative having a quinazoline-dione skeleton, one which comprises the steps of applying a phenylalanine derivative onto a solid phase of a resin to thus construct a quinazoline-dione skeleton through the use of an amide intermediate (see Patent Document 1 specified below).
Moreover, the applicant of this invention has likewise found out an industrially favorable production method of such a derivative and has already filed a patent application (see Patent Document 2 specified below). In this patent application, there has been reported a method comprising the steps of reacting an anthranilic acid derivative whose carboxyl group is protected through an ester bond with a phenylalanine derivative and finally deriving a phenylalanine derivative having a quinazoline-dione skeleton.
Moreover, the applicant of this invention have found out a phenylalanine derivative having a novel quinazoline-dione skeleton, which shows an α-4-integrin-inhibitory action and has already filed a patent application (Patent Document 3 specified below). In this patent application, there has been reported, as a production method, a linear liquid-phase synthetic method for constituting its skeleton in succession.
However, there has still been desired for the development of a method for the preparation of a phenylalanine derivative having a quinazoline-dione skeleton, which is industrially favorable as well as a further synthetic route which has not yet been known. More specifically, there has been desired for the development of a method for preparing the same while accomplishing a variety of merits, for instance, the synthetic route being convergent; the method requiring a small number of steps for the preparation of a final compound starting from a raw material; the method requiring a short period time for the formation of the final product; and the method permitting the production of the final compound in a higher yield; and the resulting final compound being highly pure.    Patent Document 1: WO 02/16329;    Patent Document 2: WO 2004/74264;    Patent Document 3: WO 2005/61466